4-hydroxy-n-desmethyltamoxifen and Melanoma

The use of the antiestrogen tamoxifen in melanoma therapy is controversial due to the unsuccessful outcomes and a still rather unclarified mechanism of action. It seemed that the days of tamoxifen in malignant melanoma therapy were close to an end, but new evidence may challenge this fate. On one hand, it is now believed that metabolism is a major determinant of tamoxifen clinical outcomes in breast cancer patients, which is a variable that has yet to be tested in melanoma patients, since the tamoxifen active metabolite endoxifen demonstrated superior cytostatic activity over the parent drug in melanoma cells; on the other hand, new evidence has emerged regarding estrogen-mediated signaling in melanoma cells, including the methylation of the estrogen receptor-α gene promoter and the expression of the G protein coupled estrogen receptor. The expression of estrogen receptor-α and G protein coupled estrogen receptor, as well as the cytochrome P450 (CYP) 2D6 genotype, may be used as predictive biomarkers to select the patients that may respond to antiestrogens based on specific traits of their tumors. This review focused on these new evidences and how they may contribute to shed new light on this long-lasting controversy, as well as their possible implications for future investigations.

Topics: Animals; Antineoplastic Agents, Hormonal; Biotransformation; Cytochrome P-450 CYP2D6; Estrogen Antagonists; Estrogen Receptor alpha; Genotype; Humans; Melanoma; Receptors, Estrogen; Receptors, G-Protein-Coupled; Signal Transduction; Skin Neoplasms; Tamoxifen

Recent reports suggest that N-methyl-d-aspartate receptor (NMDAR) blockade by MK-801 decreases tumor growth. Thus, we investigated whether other ionotropic glutamate receptor (iGluR) antagonists were also able to modulate the proliferation of melanoma cells. On the other hand, the antiestrogen tamoxifen (TAM) decreases the proliferation of melanoma cells, and is included in combined therapies for melanoma. As the efficacy of TAM is limited by its metabolism, we investigated the effects of the NMDAR antagonist MK-801 in combination with TAM and its active metabolites, 4-hydroxytamoxifen (OHTAM) and endoxifen (EDX). The NMDAR blockers MK-801 and memantine decreased mouse melanoma K1735-M2 cell proliferation. In contrast, the NMDAR competitive antagonist APV and the AMPA and kainate receptor antagonist NBQX did not affect cell proliferation, suggesting that among the iGluR antagonists only the NMDAR channel blockers inhibit melanoma cell proliferation. The combination of antiestrogens with MK-801 potentiated their individual effects on cell biomass due to diminished cell proliferation, since it decreased the cell number and DNA synthesis without increasing cell death. Importantly, TAM metabolites combined with MK-801 promoted cell cycle arrest in G1. Therefore, the data obtained suggest that the activity of MK-801 and antiestrogens in K1735-M2 cells is greatly enhanced when used in combination.

Topics: Animals; Antineoplastic Agents, Hormonal; Cell Proliferation; Dizocilpine Maleate; Drug Evaluation, Preclinical; Drug Therapy, Combination; Excitatory Amino Acid Antagonists; Melanoma; Mice; Tamoxifen; Tumor Cells, Cultured

Melanoma incidence is dramatically increasing and the available treatments beyond partial efficacy have severe side effects. Retinoids are promising anticancer agents, but their clinical use has been limited by their toxicity, although a combination with other agents can possibly generate a therapeutic action at lower dosage. Thus, we investigated the effects of all-trans-retinoic acid combined with the antiestrogen endoxifen on melanoma cell proliferation and the effects were compared with its pro-drug tamoxifen. Moreover, we evaluated the effects of these combinations on non-neoplasic cells and assessed mitochondrial bioenergetic functions, to predict their potential toxicity. Individually, all-trans-retinoic acid and the antiestrogens endoxifen and tamoxifen decreased melanoma cell biomass, cell viability and DNA synthesis, without increased cell death, suggesting that the compounds inhibited cell proliferation. Noteworthy, endoxifen decreased cell proliferation more efficiently than tamoxifen. The combination of endoxifen with all-trans-retinoic acid enhanced the antiproliferative effects of the compounds individually more potently than tamoxifen, which did not enhance the effects induced by all-trans-retinoic acid alone, and blocked cell cycle progression in G1. Moreover, the combination of all-trans-retinoic acid with endoxifen significantly decreased melanoma cells migration, whereas the combination with tamoxifen did not present significant effects. At the concentrations used the compounds did not induce cytotoxicity in non-neoplasic cells and liver mitochondrial bioenergetic function was not affected. Altogether, our results show for the first time that a combined treatment of all-trans-retinoic acid with endoxifen may provide an anti-proliferative and anti-migration effect upon melanoma cells without major toxicity, offering a powerful therapeutic strategy for malignant melanoma.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Cell Movement; Cell Proliferation; Energy Metabolism; Estrogen Receptor Modulators; Female; Liver; Male; Melanoma; Mice; Mitochondria; Rats; Tamoxifen; Tretinoin; Xenograft Model Antitumor Assays